Ienglam Lei1, Zhong Wang1, Y Eugene Chen1, Peter X Ma2,3,4, Wei Huang1, Elaine Kim1, Hugo Y K Lam5, Daniel R Goldstein6, Keith D Aaronson6, Francis D Pagani1, Paul C Tang1. 1. Department of Cardiac Surgery (I.L., Z.W., Y.E.C., W.H., E.K., F.D.P., P.C.T.). 2. Department of Biomedical Engineering (P.X.M). 3. School of Dentistry (P.X.M.). 4. Department of Biologic and Materials Sciences (P.X.M.). 5. University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI. HypaHub, Inc (H.Y.K.L.). 6. Division of Cardiovascular Medicine (D.R.G., K.D.A.).
Abstract
BACKGROUND: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. METHODS: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. RESULTS: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. CONCLUSIONS: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.
BACKGROUND: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. METHODS: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. RESULTS: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. CONCLUSIONS: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.
Authors: Susan R Scott; Keith L March; I-Wen Wang; Kanhaiya Singh; Jianyun Liu; Mark Turrentine; Chandan K Sen; Meijing Wang Journal: J Mol Cell Cardiol Date: 2021-11-11 Impact factor: 5.000
Authors: Ienglam Lei; Wei Huang; Peter A Ward; Jordan S Pober; George Tellides; Gorav Ailawadi; Francis D Pagani; Andrew P Landstrom; Zhong Wang; Richard M Mortensen; Marilia Cascalho; Jeffrey Platt; Yuqing Eugene Chen; Hugo Yu Kor Lam; Paul C Tang Journal: Physiol Rep Date: 2021-09
Authors: Paul C Tang; Xiaoting Wu; Min Zhang; Donald Likosky; Jonathan W Haft; Ienglam Lei; Ashraf Abou El Ela; Ming-Sing Si; Keith D Aaronson; Francis D Pagani Journal: J Card Surg Date: 2022-04-30 Impact factor: 1.778